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Effects of aneuploidy on cell behaviour and function

Nature Reviews Molecular Cell Biology volume 23, pages 250–265 (2022)Cite this article

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Abstract

Aneuploidy, a genomic alternation characterized by deviations in the copy number of chromosomes, affects organisms from early development through to aging. Although it is a main cause of human pregnancy loss and a hallmark of cancer, how aneuploidy affects cellular function has been elusive. The last two decades have seen rapid advances in the understanding of the causes and consequences of aneuploidy at the molecular and cellular levels. These studies have uncovered effects of aneuploidy that can be beneficial or detrimental to cells and organisms in an environmental context-dependent and karyotype-dependent manner. Aneuploidy also imposes general stress on cells that stems from an imbalanced genome and, consequently, also an imbalanced proteome. These insights provide the fundamental framework for understanding the impact of aneuploidy in genome evolution, human pathogenesis and drug resistance.

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Fig. 1: A brief history of major advances in the research on aneuploidy.
Fig. 2: Defects in spindle function and regulation that can give rise to aneuploidy.
Fig. 3: Diverse stresses can impair the fidelity of chromosome segregation.
Fig. 4: Karyotype-specific effects on gene expression.
Fig. 5: System-wide and general effects of aneuploidy due to proteome imbalance.
Fig. 6: Potential mechanisms by which aneuploidy drives tumorigenesis.

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Acknowledgements

The authors thank A. Holland (Johns Hopkins University School of Medicine) and M. Gordon (Johns Hopkins University School of Medicine) for valuable comments on the manuscript.

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Authors and Affiliations

  1. Mechanobiology Institute, National University of Singapore, Singapore, Singapore

    Rong Li & Jin Zhu

  2. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Rong Li

  3. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rong Li

  4. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA

    Rong Li

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  1. Rong Li
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Supplementary information

Glossary

Trisomy 21

(T21). The genetic abnormality characterized by an extra copy of chromosome 21 that causes Down syndrome, the most common chromosomal disorder, affecting roughly 1 in 700 human babies born.

Cellular senescence

Irreversible exist from the cell cycle usually in response to diverse stress.

Euploid

The state of having complete sets of chromosomes in eukaryotic cells.

Merotelic attachments

Erroneous kinetochore–microtubule attachments where one kinetochore is attached to microtubules from both spindle poles.

Pericentriolar material

A complex set of proteins surrounding the centrioles that harbour the microtubule-nucleating activity of centrosomes.

Cohesin

A ring-like structure that is loaded onto chromosomes at the time of DNA replication and maintains cohesion between sister chromotids until chromosome segregation occurs.

Mosaic loss

Chromosomal loss events resulting in mosaicism.

Replication forks

Structures organized by helicase and other DNA replication-related proteins that allow replication of each strand.

Ultrafine DNA bridges

(UFBs). Thin DNA structures that link separating sister chromatids in mitosis.

R loops

Nucleic acid structures consisting of a DNA–RNA hybrid and a displaced single-stranded DNA that normally form during transcription and DNA replication but that are also present in mitotic cells.

X chromosome inactivation

The phenomenon of random inactivation of one of the two X chromosomes during development in females.

CpG sites

Regions of DNA where a cytosine (C) is followed by a guanine (G) and the cytosine is frequently methylated in mammals.

DNA methyltransferase DNMT3L

A member of the DNA methyltransferase family that lacks a catalytic domain and functions as a stimulating cofactor for DNA methylation.

HMGN1

A nucleosomal DNA-binding protein that modulates open chromatin structure and promotes transcription.

Sir2

The yeast nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase that catalyses the removal of acetyl groups from acetyllysine residues.

Subtelomeric regions

Regions on the chromosome of unique DNA sequence characteristics that are immediately adjacent to the telomeres, specialized structures defining chromosome ends.

Myosin II

A conserved actin-based motor protein that drives cytokinetic ring contraction in diverse eukaryotic cells.

Environmental stress response

A common yeast gene expression programme involving ~900 genes responding to multiple stresses.

Translesion synthesis

A process in which specialized DNA polymerases synthesize a short patch of DNA to bypass blocking DNA lesions.

Chromothripsis

Massive chromosome rearrangements that result in abnormal chromosomes containing multiple segments from different chromosomes.

Aggresome

An intracellular structures made up of aggregated misfolded proteins.

Unfolded protein response

An integrated intracellular signalling pathway responding to the burden of unfolded proteins in the endoplasmic reticulum lumen.

Somatic evolution

Genetic and epigenetic changes in the clonal composition of somatic cells in tissues over time resulting from evolutionary selection.

Acute megakaryoblastic leukaemia

A subtype of acute myeloid leukaemia characterized by abnormal megakaryoblasts.

Clonogenicity

The ability of cells to grow and form colonies.

Oncogene addiction

Dependence of cancers on specific oncogenic mutations to survive and/or proliferate.

Triple-negative breast cancers

Breast cancers that test negative for oestrogen receptors, progesterone receptors and excess HER2 protein.

Adult stem cells

Stem cells in adult tissues that are capable of self-renewal and differentiate into more specialized cell types.

cGAS–STING pathway

A cytosolic DNA sensing mechanism that triggers inflammatory responses.

Innate immune system

Part of the immune system that forms the first line of defence against pathogens (consisting of physical, chemical and cellular mechanisms).

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Li, R., Zhu, J. Effects of aneuploidy on cell behaviour and function. Nat Rev Mol Cell Biol 23, 250–265 (2022). https://doi.org/10.1038/s41580-021-00436-9

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